Extended cycle streptozotocin/5-FU chemotherapy for maintenance therapy in pancreatic neuroendocrine tumors.

PURPOSE: The standard of care treatment for patients with advanced pancreatic neuroendocrine tumors (pNET) is a combination of streptozotocin and 5-FU. Although widely used, little is known about the best long-term strategy with these substances. METHODS: We here report our experience of 28 patients treated with streptozotocin/5-FU for advanced pNET with special consideration for long-term management using an extended cycle protocol. RESULTS: Standard 6-weekly Moertel protocol resulted in a median progression-free survival of 21 months (range 3-128) and a median overall survival of 69 months (range 3-157+) in the whole cohort. Thirteen of the 28 patients were switched to an extended 3-month cycle protocol for maintenance therapy. Of these 13 patients, 2 achieved complete remission, 1 partial remission, and 8 stable disease as best response while 2 showed progressive disease following switch to the extended protocol, resulting in an additional median progression-free survival of 23 months. Median overall survival after the start of chemotherapy in this patient group was 69 months (21-157+). Patients benefitted from extended periods free of chemotherapy-associated side effects after switching to the extended cycle protocol. CONCLUSIONS: Switching to an extended cycle protocol of 3 months for maintenance therapy following initial standard cycles may achieve long-term disease stabilization in selected patients with advanced pNET with good patient acceptance.

Impaired gastric acidification negatively affects calcium homeostasis and bone mass.

Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. Here we show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells, have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia. These results suggest that alterations in calcium homeostasis can be driven by defects in gastric acidification, especially given that calcium gluconate supplementation fully rescues the phenotype of the Cckbr-mutant mice. Finally, mice deficient in Tcirg1, encoding a subunit of the vacuolar proton pump specifically expressed in both osteoclasts and parietal cells, show hypocalcemia and osteopetrorickets. Although neither Src- nor Cckbr-deficient mice have this latter phenotype, the combined deficiency of both genes results in osteopetrorickets. Thus, we find that osteopetrosis and osteopetrorickets are distinct phenotypes, depending on the site or sites of defective acidification.